Immunity to malaria after administration of ultra-low doses of red cells infected with Plasmodium falciparum

Pombo, David; Lawrence, Gregory J.; Hirunpetcharat, Chakrit; Rzepczyk, Christine M.; Bryden, Michelle; Cloonan, Nicole; Anderson, Karen; Mahakunkijcharoen, Yuvadee; Martin, Laura B.; Wilson, Danny W.; Elliott, Salenna R.; Elliott, Suzanne; Eisen, Damon P.; Weinberg, J. Brice; Saul, Allan; Good, Michael F.

doi:10.1016/s0140-6736(02)09784-2

Cited by 376 publications

(364 citation statements)

References 30 publications

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“…A protective role for IFN-g-secreting effector T cells is well established and has been exploited in numerous vaccination approaches [4][5][6]. Indeed, in one particular study volunteers were immunized with low doses of Plasmodium-infected RBC (iRBC), and they produced T-cell IFN-g responses against blood-stage Ag that were associated with protection from challenge in the absence of Ab responses [7]. A frequently described observation is the apparently short-lived immunity generated after exposure to the parasite [8,9], which may be a result of depressed cellular immunity [10,11].…”

Section: Introductionmentioning

confidence: 99%

Multiple functions of human T cells generated by experimental malaria challenge

et al. 2009

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Protective immunity generated following malaria infection may be comprised of Ab or T cells against malaria Ag of different stages; however, the short-lived immunity that is observed suggests deficiency in immune memory or regulatory activity. In this study, cellular immune responses were investigated in individuals receiving Plasmodium falciparum sporozoite challenge by the natural (mosquito bite) route as part of a malaria vaccine efficacy trial. Parasitemia, monitored by blood film microscopy and PCR, was subsequently cleared with drugs. All individuals demonstrated stable IFN-c, IL-2 and IL-4 ex vivo ELISPOT effector responses against P. falciparum-infected RBC (iRBC) Ag, 28 and 90 days after challenge. However, infected RBC-specific central memory responses, as measured by IFN-c cultured ELISPOT, were low and unstable over time, despite CD4 1 T cells being highly proliferative by CFSE dilution, and showed an inverse relationship to parasite density. In support of the observation of poor memory, co-culture experiments showed reduced responses to common recall Ag, indicating malaria-specific regulatory activity. This activity could not be accounted for by the expression of IL-10, TGF-b, FOXP3 or CTLA-4, but proliferating T cells expressed high levels of CD95, indicating a pro-apoptotic phenotype. Lastly, there was an inverse relationship between FOXP3 expression, when measured 10 days after challenge, and ex vivo IFN-c measured more than 100 days later. This study shows that malaria infection elicits specific Th1 and Th2 effector cells, but concomitant weak central memory and regulatory activity, which may help to explain the short-lived immunity observed.

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Section: Introductionmentioning

confidence: 99%

Multiple functions of human T cells generated by experimental malaria challenge

et al. 2009

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“…Second, experimental infections of non-immune volunteers with an ultra-low dose of infected RBC induce immunity to subsequent challenge in the absence of detectable antibody responses. Those who acquire immunity show proliferative responses in CD8 1 T cells [12].…”

Section: Introductionmentioning

confidence: 99%

Involvement of CD8⁺ T cells in protective immunity against murine blood‐stage infection with Plasmodium yoelii 17XL strain

et al. 2010

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When developing malaria vaccines, the most crucial step is to elucidate the mechanisms involved in protective immunity against the parasites. We found that CD8+ T cells contribute to protective immunity against infection with blood‐stage parasites of Plasmodium yoelii. Infection of C57BL/6 mice with P. yoelii 17XL was lethal, while all mice infected with a low‐virulence strain of the parasite 17XNL acquired complete resistance against re‐infection with P. yoelii 17XL. However, the host mice transferred with CD8+ T cells from mice primed only with P. yoelii 17XNL failed to acquire protective immunity. On the other hand, the irradiated host mice were completely resistant to P. yoelii 17XL infection, showing no grade of parasitemia when adoptively transferred with CD8+ T cells from immune mice that survived infection with both P. yoelii XNL and, subsequently, P. yoelii 17XL. These protective CD8+ T cells from immune WT mice had the potential to generate IFN‐γ, perforin (PFN) and granzyme B. When mice deficient in IFN‐γ were used as donor mice for CD8+ T cells, protective immunity in the host mice was fully abrogated, and the immunity was profoundly attenuated in PFN‐deficient mice. Thus, CD8+ T cells producing IFN‐γ and PFN appear to be involved in protective immunity against infection with blood‐stage malaria.

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“…Recent studies have shown an increased interest in the possibility of generating vaccine-induced protective immunity to blood-stage malaria [6] through induction of a protective T cell response that can act independently of antibody [35,36]. However, allelic polymorphism in malaria antigens presents a dilemma for vaccine design.…”

Section: Discussionmentioning

confidence: 99%

Dimorphic Plasmodium falciparum merozoite surface protein‐1 epitopes turn off memory T cells and interfere with T cell priming

et al. 2006

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The leading blood-stage malaria vaccine candidate antigen, Plasmodium falciparum merozoite surface protein-1 (MSP-1) occurs in two major allelic types worldwide. The molecular basis promoting this stable dimorphism is unknown. In this study, we have shown that allelic altered peptide ligand (APL) T cell epitopes of MSP-1 mutually inhibited IFN-c secretion as well as proliferation of CD4 + T cells in 27/34 malaria exposed Gambian volunteers. Besides this inhibition of malaria-specific immunity, the same variant epitopes were also able to impair the priming of human T cells in malaria naive individuals. Epitope variants capable of interfering with T cell priming as well as inhibiting memory T cell effector functions offer a uniquely potent combination for immune evasion. Indeed, enhanced co-habitation of parasites bearing such antagonistic allelic epitope regions was observed in a study of 321 West African children, indicating a survival advantage for parasites able to engage this inhibitory immune interference mechanism.

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Immunity to malaria after administration of ultra-low doses of red cells infected with Plasmodium falciparum

Cited by 376 publications

References 30 publications

Multiple functions of human T cells generated by experimental malaria challenge

Multiple functions of human T cells generated by experimental malaria challenge

Involvement of CD8⁺ T cells in protective immunity against murine blood‐stage infection with Plasmodium yoelii 17XL strain

Dimorphic Plasmodium falciparum merozoite surface protein‐1 epitopes turn off memory T cells and interfere with T cell priming

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Immunity to malaria after administration of ultra-low doses of red cells infected with Plasmodium falciparum

Cited by 376 publications

References 30 publications

Multiple functions of human T cells generated by experimental malaria challenge

Multiple functions of human T cells generated by experimental malaria challenge

Involvement of CD8+ T cells in protective immunity against murine blood‐stage infection with Plasmodium yoelii 17XL strain

Dimorphic Plasmodium falciparum merozoite surface protein‐1 epitopes turn off memory T cells and interfere with T cell priming

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Involvement of CD8⁺ T cells in protective immunity against murine blood‐stage infection with Plasmodium yoelii 17XL strain